This project seeks to improve the clinical care available to patients with disorders of ovarian follicle function and ovulation through research using animal models and clinical protocols. In pursuing this goal, we expect to expand understanding of the ovarian follicle in health and disease. We have focused on premature ovarian failure, a condition that prematurely terminates ovarian function and fertility in 1% of women. During this period we found that femoral neck bone density is significantly reduced in women with premature ovarian failure. Surprisingly, more than one-half of our patients had a bone density low enough to cause a threefold increase their risk of fracture. Inappropriate luteinization of graafian follicles appears to be a major pathophysiologic mechanism in patients with karyotypically normal spontaneous premature ovarian failure. Strikingly, we found luteinized graafian follicles in all the antral follicles we biopsied in 6 patients with karyotypically normal spontaneous premature ovarian failure. Therefore, luteinized graafian follicles account for at least 60% of the antral structures imaged (95% confidence limit). We have particular interest in autoimmune ovarian failure. Using an animal model, we found that autoantibodies from mice with experimental autoimmune oophoritis bind to a 120 kd protein that is specific to the oocyte cytoplasm. By screening a mouse ovarian cDNA expression library with this serum, we identified a novel oocyte-specific gene that may represent the inciting antigen in this disease. Also, we showed that the inciting ovarian antigen in murine experimental autoimmune oophoritis appears to be produced independently of gonadotropin stimulation. By administering gonadotropin stimulation or suppression to neonatally thymectomized mice we did not alter the course of the disease. During this period we also found that the lymphocytic infiltration in murine experimental autoimmune oophoritis is primarily localized in the stroma and theca, and does not involve a direct lymphocytic attack against intact oocytes. Intriquingly, our investigations in murine post-thymectomy polyglandular autoimmunity suggest that neonatal thymectomy causes a deficiency of CD4+ T helper 1 (Th1) activity that persists into adulthood. In ongoing work we are testing the hypothesis that this Th1-deficient state induces the autoimmune disease. We will also determine, using transgenic technology, if the novel oocyte-specific gene is the inciting ovarian antigen in murine experimental autoimmune oophoritis. Future clinical directions involve developing strategies to increase bone density in women with premature ovarian failure, a treatment to prevent inappropriate luteinization in patients with premature ovarian failure, and a protocol to test the hypothesis that inappropriate luteinization plays a role in the infertility of maturing women.